Synthesis,molecular docking and biological evaluation of some benzimidazole derivatives as potent pancreatic lipase inhibitors

In this study, a new series of benzimidazole and bisbenzimidazole derivatives were prepared via the reaction of iminoester hydrochlorides and o-phenylenediamines and then screened for their lipase inhibition properties. Among the synthesized molecules, compounds 7a, 8a and 8c showed the best inhibitory effect against lipase enzyme with IC₅₀ values of 1.72 ± 0.12 µM, 1.92 ± 0.28 and 0.98 ± 0.07 µM, respectively. Moreover, molecular modeling studies were performed in order to understand to the inhibitory activity of the molecules. Binding poses of the studied compounds were determined at the target sites using induced fit docking (IFD) algorithms.     

Synthesis and biological evaluation of some dibenzofuran-piperazine derivatives

In the present paper, a novel series of dibenzofuran-piperazine derivatives were synthesized via the treatment of N-(2-methoxy-3-dibenzofuranyl)-2-chloroacetamide with substituted piperazine derivatives. The chemical structures of the compounds were elucidated by ¹H NMR, ¹³C NMR, mass spectral data; elemental analysis and HPLC analysis. Each derivative was evaluated for antiplatelet activity and anticholinesterase activity. Compound 2?m with 2-furoyl moiety exhibited high percentage inhibition as much as standard drug aspirin on arachidonic acid (AA)-induced platelet aggregation. None of the compounds presented significant inhibitor effect on collagen-induced platelet aggregation. Furthermore, the anticholinesterase activity of the compounds was determined and they did not show promising inhibitor activity compared with standard drug donepezil.     

Biocatalytic synthesis,structural elucidation,antioxidant capacity and tyrosinase inhibition activity of long chain fatty acid acylated derivatives of phloridzin and isoquercitrin

Our present investigation describes the regioselective enzymatic acylation of two series of acylated derivatives of phloridzin and isoquercitrin with six different long chain saturated, mono- and poly-unsaturated fatty acids. The biocatalytic synthesis was optimized to achieve 81–98% yields, using immobilized lipase B, from Candida antarctica (Novozym 435®), in acetone at 45 °C. The synthesized esters have been analyzed by ¹H NMR, ¹³C NMR spectroscopy and evaluated for their antioxidant capacity and tyrosinase inhibition, using in vitro assays. Among all the phloridzin and isoquercitrin derivatives, the greatest potential for inhibition of tyrosinase activity (p ?0.05) was exhibited by the α-linolenic acid ester of isoquercitrin.     

Synthesis and biological evaluation of new pyrazolone Schiff bases as monoamine oxidase and cholinesterase inhibitors

In the current work, Schiff base derivatives of antipyrine were synthesized. The chemical characterization of the compounds was confirmed using IR, ¹H NMR, ¹³C NMR and mass spectroscopies. The inhibitory potency of synthesized compounds was investigated towards acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidases A and B (MAO-A and MAO-B) enzymes. Some of the compounds displayed significant inhibitory activity against AChE and MAO-B enzymes, respectively. According to AChE enzyme inhibition assay, compounds 3e and 3g were found as the most potent derivatives with IC₅₀ values of 0.285 µM and 0.057 µM, respectively. Also, compounds 3a (IC₅₀ = 0.114 µM), 3h (IC₅₀ = 0.049 µM), and 3i (IC₅₀ = 0.054 µM) were the most active derivatives against MAO-B enzyme activity. So as to understand inhibition type, enzyme kinetics studies were carried out. Furthermore, molecular docking studies were performed to define and evaluate the interaction mechanism between compounds 3g and 3h and related enzymes. ADME (Absorption, Distribution, Metabolism, and Excretion) and BBB (Blood, Brain, Barier) permeability predictions were applied to estimate pharmacokinetic profiles of synthesized compounds.     

5-Thioxoimidazolidine-2-one derivatives: Synthesis,anti-inflammatory activity,analgesic activity,COX inhibition assay and molecular modelling study

A series of 5-imino-4-thioxo-2-imidazolidinone derivatives with different substituents at N¹ and N³ was synthesized with high yield and excellent purity by the reaction of different N-arylcyanothioformamide derivatives with isocyanate derivatives. Treatment 5-imino-4-thioxo-2-imidazolidinone derivatives with acidic medium afforded 4-thioxoimidazolidin-2,5-dione derivatives. The structures of the obtained products were established based on spectroscopic IR, ¹H NMR, ¹³C NMR, ¹H, ¹H-COSY, HSQC and elemental analyses. The anti-inflammatory activity of the synthesized compounds through the carrageenan-paw edema model as well as in vitro COX-1 and COX-2 inhibition assay were evaluated where most of the synthesized compounds showed significant anti-inflammatory activity. Mostly, all of our synthesized compounds have greater activity more than celecoxib toward both cyclooxygenase enzymes. All of the tested compounds (except one compound) exhibited IC₅₀ valves for COX-2 ranged from 0.001 × 10⁻³ to 0.827 × 10⁻³ µM while the reference drug has IC₅₀ 40.0 × 10⁻³ µM. Furthermore, the analgesic activity of such compounds was also determined. Molecular modeling study was also conducted to rationalize the potential as anti-inflammatory agents of our synthesized compounds by predicting their binding modes, binding affinities and optimal orientation at the active site of the COX enzymes.     

Piperazine-azole-fluoroquinolone hybrids: Conventional and microwave irradiated synthesis,biological activity screening and molecular docking studies

A series of new 1,2,4-triazole and 1,3,4-oxadiazole derivatives was obtained via several steps sequential reactions of phenyl piperazine. Then, these compounds were converted to the corresponding fluoroquinolone hybrids via one pot three component Mannich reaction. All the reactions were examined under conventional and microwave mediated conditions, and optimum conditions were determined. The effect of different solvents and microwave power on microwave prompted reactions was investigated as well. All the newly synthesized compounds were characterized by FTIR, ¹H NMR, ¹³C NMR and EI MS spectral techniques. The antimicrobial activity, DNA gyrase and Topoisomerase IV inhibition potentials were performed. The results obtained showed that fluoroquinolone hybrids possess good antimicrobial activity. Moreover, Fluoroquinolone-azole-piperazine hybrids synthesized in the present study displayed excellent DNA gyrase inhibition. To unveil the interaction mode of compounds to receptor, a molecular docking study was performed. With an average least binding energy of −9.5 kcal/mol, all compounds were found to have remarkable inhibitory potentials against DNA gyrase (E. coli).     

Synthesis of sulfanilamide derivatives and investigation of in vitro inhibitory activities and antimicrobial and physical properties

Novel sulfanilamide derivatives were synthesized and evaluated for carbonic anhydrase inhibitory activity as a target for the treatment of glaucoma, and antibacterial properties for use in chemotherapy. Synthesized compounds were characterized by FT-IR, ¹H NMR, ¹³C NMR and photoluminescence. In vitro inhibitory activities were measured by UV-Vis and some of the compounds were found have greater inhibitory effects than the lead compound sulfanilamide. The correlation between inhibitory activity, biological properties and the physicochemical properties of water solubility and partition coefficients was also investigated. Sulfanilamide derivatives gave intense emissions upon irradiation by UV light and a dimethyl substituted compound and a cyclic analog have photoluminescence quantum yields 42% and 31% and long excited-state lifetimes of 3.92 and 2.91 ns, respectively.     

Synthesis,molecular docking study and in vitro thymidine phosphorylase inhibitory potential of oxadiazole derivatives

We have synthesized oxadiazole derivatives (1–16), characterized by ¹H NMR, ¹³C NMR and HREI-MS and screened for thymidine phosphorylase inhibitory potential. All derivatives display varied degree of thymidine phosphorylase inhibition in the range of 1.10 ± 0.05 to 49.60 ± 1.30 μM when compared with the standard inhibitor 7-Deazaxanthine having an IC₅₀ value 38.68 ± 1.12 μM. Structure activity relationships (SAR) has been established for all compounds to explore the role of substitution and nature of functional group attached to the phenyl ring which applies imperious effect on thymidine phosphorylase activity. Molecular docking study was performed to understand the binding interaction of the most active derivatives with enzyme active site.     

Synthesis,Conformational and Configurational Studies of Some New Acetylated Glycosides of 2-Thio-3-aryl-4(3H)-quinazolinones,Their Thiono and 3,1-Benzothiazin-2,4-dithione

Abstract

A series of some new acetylated S-glycosides of 2-thioxoquinazolin-4-ones, their thiono analogues and 3,1-benzothazin-2,4-dithione derivatives, including a D-glucose and a D-galactose derivatives and a D-xylose, and an L-arabinose derivatives have been synthesized. The conformation and configuration of these carbohydrate derivatives were determined by analysing their ¹H and ¹³C NMR chemical shifts and coupling constants. The biological activity of these compounds has been studied.     

Bioinorganic chemistry aspects of the inhibition of thyroid hormone biosynthesis by anti-hyperthyroid drugs

In this paper, the synthesis and characterization of thiones and selones having N,N-disubstituted imidazole are described. Experimental and theoretical studies were performed on a number of selones, which suggest that these compounds exist as zwitterions in which the selenium atom carries a large negative charge. The structures of selones were studied in solution by ⁷⁷Se NMR spectroscopy and the ⁷⁷Se NMR chemical shifts for the selones show large upfield shifts in the signals, confirming the zwitterionic structure of the selones in solution. The thermal isomerization of some S- and Se-substituted methyl and benzyl imidazole derivatives to produce the thermodynamically more stable N-substituted derivatives are described. A structure-activity correlation was attempted on the inhibition of LPO-catalyzed oxidation and iodination reactions by several thiouracil compounds, which indicate that the presence of an n-propyl group in PTU is important for an efficient inhibition. In contrast to the S- and Se-substituted derivatives, the selones produced by thermal isomerization exhibited efficient inhibition, indicating the importance of reactive selone (zwitterionic) moiety in the inhibition. The inhibition data on carbimazole (CBZ) support the assumption that CBZ acts as a prodrug, requiring a conversion to methimazole (MMI) for its inhibitory action on thyroid peroxidase.     

Synthesis and in Vitro Antimicrobial Activity Screening of New 3‐Acetyl‐2,5‐disubstituted‐1,3,4‐oxadiazoline Derivatives

Thirteen new 3‐acetyl‐2,5‐disubstituted‐1,3,4‐oxadiazoline derivatives were synthesized from corresponding hydrazide‐hydrazones of isonicotinic acid in the reaction with acetic anhydride. The obtained compounds were identified with the use of spectral methods (IR, ¹H‐NMR, ¹³C‐NMR, MS). In vitro antimicrobial activity screening of synthesized compounds against a panel of bacteria and fungi revealed interesting antibacterial and antifungal activity of tested 1,3,4‐oxadiazoline derivatives, which is comparable to that of commonly used antimicrobial agents.     

Design,synthesis, evaluation,and molecular docking of ursolic acid derivatives containing a nitrogen heterocycle as anti-inflammatory agents

Ursolic acid derivatives containing oxadiazole, triazolone, and piperazine moieties were synthesized in an attempt to develop potent anti-inflammatory agents. Structures of the synthesized compounds were elucidated by ¹H NMR, ¹³C NMR, and HRMS. Most of the synthesized compounds showed pronounced anti-inflammatory effects at 100?mg/kg. In particular, compound 11b, which displayed the most potent anti-inflammatory activity of all of the compounds prepared, with 69.76% inhibition after intraperitoneal administration, was more potent than the reference drugs indomethacin and ibuprofen. The cytotoxicity of the compounds was also assessed by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and no compounds showed any appreciable cytotoxic activity (IC₅₀ >100?μmol/L). Furthermore, molecular docking studies of the synthesized compounds were performed to rationalize the obtained biological results. Overall, the results indicate that compound 11b could be a therapeutic candidate for the treatment of inflammation.     

Novel 3-pyridinecarbonitriles incorporating sulfonamide moieties as anti-breast cancer agents

A novel series of 3-pyridinecarbonitrile derivatives incorporating sulfonamide moieties and sulfonyl derivatives was synthesized using 2-chloro-6-methylnicotinonitrile as a strategic starting material. The structures of the synthesized compounds were elucidated on the basis of elemental analysis, IR, ¹H NMR, ¹³C NMR, and mass spectral data. All the prepared compounds were evaluated for their in vitro anticancer activity against breast cancer cell line (MCF-7). Most of the compounds showed good to moderate activity, higher than that of the reference drug doxorubicin. Two compounds showed the same activity as doxorubicin, while three compounds exhibited remarkable activity.     

New pentadienone oxime ester derivatives: synthesis and anti-inflammatory activity

To develop novel anti-inflammatory agents, a series of new pentadienone oxime ester compounds were designed and synthesized. The structures were determined by IR, ¹H NMR, ^13?C NMR, and HRMS. All compounds have been screened for their anti-inflammatory activity by evaluating their inhibition against LPS-induced nitric oxide (NO) release in RAW 264.7 cell. Among them, compound 5j was found to be one of the most potent compounds in inhibiting NO and IL-6 (IC₅₀ values were 6.66?µM and 5.07?µM, respectively). Preliminary mechanism studies show that title compound 5j could significantly suppress expressions of nitric oxide synthase, COX-2, and NO, IL-6 through Toll-like receptor 4/mitogen-activated protein kinases/NF-κB signalling pathway. These data support further studies to assess rational design of more efficient pentadienone oxime ester derivatives with anti-inflammatory activity in the future.     

Design,synthesis, anti-inflammatory activity and molecular docking of potential novel antipyrine and pyrazolone analogs as cyclooxygenase enzyme (COX) inhibitors

As a part of a directed program for development of new active agents, novel heterocyclic derivatives with antipyrine and pyrazolone moieties -incorporated in- have been designed and synthesized. Starting with 4-arylidene-3-methyl-1-phenyl-5-pyrazolone derivative 2a,b novel Mannich bases derivatives have been synthesized and biologically evaluated for their anti-inflammatory activity. Furthermore, the activity of such compounds has been tested interestingly as COX-1 and COX-2 inhibitors. Structure elucidation of the synthesized compounds was attained by the use of elemental analysis, IR, ¹H NMR, ¹³C NMR, and Mass spectrometry techniques. Compounds 3b, 3d and 4b represent the high % inhibition values for both COX-1 and COX-2. On the other hand, compound 8 showed little selectivity against COX-2 while compound 10 showed good selectivity against COX-1 only. Structure activity relationship has been discussed and the results were confirmed by molecular docking calculations.     

Three new flavones from the roots and stems of Tiandeng tobacco and their anti-TMV activities

Three new flavone derivatives, paranicflavones A–C (1–3), together with three known similar compounds (4–6), were isolated from their roots and stems of Tiandeng tobacco. Their structures were elucidated by spectroscopic methods, including extensive ¹H and ¹³C NMR techniques. Additionally, compounds 1–6 were evaluated for their anti-tobacco mosaic virus (anti-TMV) activities, and compound 2 exhibited anti-TMV activity with inhibition rate of 35.8%, which is higher than that of positive control, ningnanmycin.     

Synthesis,molecular modelling and biological evaluation of tetrasubstituted thiazoles towards cholinesterase enzymes and cytotoxicity studies

Alzheimer is a neurodegenerative disease and requires the development of new scaffold to treat it. In this regard, thiazoles derivative are playing their significant role. In the current research paper we have focused our attention for the development of tetrasubstituted thiazole (3a-h) derivatives using domino synthesis by mixing the thiourea as a precursor, with acetophenone in the presence of iodine and tosic acid in DMSO and refluxed for 12–22 h. The structures of the newly synthesized compounds were confirmed by FTIR, ¹H NMR, ¹³C NMR and EIMS analysis. Thiazole derivatives were analyzed for their biological significances against acetyl and butylcholinesterase enzymes and compound 3b and 3d were found more active against these enzyme, respectively. The mode of inhibition was determined for the potent compounds against both the enzymes. Moreover, the molecular docking studies were carried out to explore the interactive behavior of the compounds within the active pocket of enzymes. Furthermore, the derivatives (3a-h) were evaluated for their anticancer potential against HeLa cancer cell lines. Most potent inhibition was observed by compound 3b.     

Design,synthesis and biological activity of pyrazinamide derivatives for anti-Mycobacterium tuberculosis

A total of 11 pyrazinamide derivatives were designed and synthesised using pyrazinamide as the lead compound, which was optimised by structural modification with alkyl chains, six-membered rings, and bioisosterism, respectively. The target compounds were synthesised using pyrazinecarboxylic acid as the starting material by acylation, amidation, and alkylation, respectively. Their structures were confirmed by ¹H NMR, ¹³C NMR, HRESIMS, and elemental analysis, respectively. The bioactivities of derivatives were assayed using bacteriostatic experiment and minimum inhibitory concentration experiment. It was showed that the derivatives had good inhibitory effect on Mycobacterium tuberculosis. The biological activity of derivative 1f was the best among all compounds, its antibacterial activity was 99.6%, and the minimum inhibitory concentration was 8.0?µg/mL.     

Harmaline and hispidin from Peganum harmala and Inonotus hispidus with binding affinity to Candida rugosa lipase: In silico and in vitro studies

The inhibitory effect of phenolic compounds and alkaloids of Inonotus hispidus and Peganum harmala on Candida rugosa lipase was investigated, also, their antioxidant activities using DPPH, ABTS and phosphomolybdenum were studied in this paper. The phenolic extracts have shown a stronger antiradical activity than the alkaloids extracts. The enzymatic inhibition produced by these extracts is described here for the first time. The results have shown that the phenolic and the alkaloid extracts are good inhibitors of C. rugosa lipase. Thus, the inhibitor molecules (harmaline and hispidin) have been isolated from P. harmala and I. hispidus. Their structures were elucidated by ¹H NMR analysis. Molecular docking has been achieved using AutoDock Vina program to discuss the nature of interactions and the mechanism of inhibition. Therefore, these isolated molecules could be used in the treatment of candidiasis.     

Triazolopyridazine derivatives: Synthesis,cytotoxic evaluation,c-Met kinase activity and molecular docking

Novel series of some triazolo[4,3-b]pyridazine derivatives were designed and synthesized. All the newly synthesized compounds were evaluated for their cytotoxic activity at 10⁻⁵ M concentration towards 60 cancer cell lines according to USA NCI protocol. Most of the synthesized compounds showed good activity against SR (leukemia) cell panel. The most active compounds, 2f and 4a were subjected for further evaluation at a five dose level screening and their efficacy for c-Met kinase inhibition was determined in vitro. Binding mode of these derivatives was explored via molecular docking.